Pre-activated antiviral innate immunity in the upper airways controls early SARS-CoV-2 infection in children

TLDR

Children experience lower SARS‑CoV‑2 infection rates and milder COVID‑19 outcomes than adults, yet the underlying protective mechanisms are unclear. The study profiled single‑cell RNA sequencing of upper‑airway tissues from SARS‑CoV‑2–negative and positive children and matched adult controls across a wide age range. Children’s airway cells exhibit pre‑activated innate immunity with elevated pattern‑recognition receptors and distinct cytotoxic T‑cell subsets, driving stronger early antiviral responses that likely underlie their milder COVID‑19 symptoms.

Abstract

Children have reduced severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection rates and a substantially lower risk for developing severe coronavirus disease 2019 compared with adults. However, the molecular mechanisms underlying protection in younger age groups remain unknown. Here we characterize the single-cell transcriptional landscape in the upper airways of SARS-CoV-2-negative (n = 18) and age-matched SARS-CoV-2-positive (n = 24) children and corresponding samples from adults (n = 44), covering an age range of 4 weeks to 77 years. Children displayed higher basal expression of relevant pattern recognition receptors such as MDA5 (IFIH1) and RIG-I (DDX58) in upper airway epithelial cells, macrophages and dendritic cells, resulting in stronger innate antiviral responses upon SARS-CoV-2 infection than in adults. We further detected distinct immune cell subpopulations including KLRC1 (NKG2A)+ cytotoxic T cells and a CD8+ T cell population with a memory phenotype occurring predominantly in children. Our study provides evidence that the airway immune cells of children are primed for virus sensing, resulting in a stronger early innate antiviral response to SARS-CoV-2 infection than in adults. Single-cell sequencing reveals pre-activated immunity as important for milder COVID-19 symptoms in children.